title: The variability of the large genomic segment of Ťahyňa orthobunyavirus and an all-atom exploration of its anti-viral drug resistance.
abstract: Ťahyňa virus (TAHV), a member of the Bunyaviridae family (California complex), is an important but neglected human mosquito-borne pathogen. The virus genome is composed of three segments, i.e., small (S), medium (M), and large (L). Previous studies on genetic variability of viruses within the California complex were focused on S and M segments, but the L segment remains relatively unstudied. To assess the genetic variation and the relation to virus phenotype we analyzed the L segment sequences of biologically diverse TAHV strains isolated in the Czech Republic and Slovakia. Phylogenetic analysis covering all available sequences of the L segment of TAHV clearly revealed two distinguished lineages, tentatively named as "European" and "Asian". The L segment strains within the European lineage are highly conserved (identity 99.3%), whilst Asian strains are more genetically diverse (identity 97%). Based on sequence comparison with other bunyaviruses, several non-synonymous nucleotide substitutions unique for TAHV in the L segment were identified. We also identified specific residue substitutions in the endonuclease domain of TAHV compared with the La Crosse virus. Since the endonuclease domain of the La Crosse virus has been resolved, we employed an all energy landscape algorithm to analyze the ligand migration of a viral polymerase inhibitor. This allowed us to demonstrate, at the atomic level, that this viral polymerase inhibitor randomly explored the specific residue substitutions in the endonuclease domain of the TAHV L segment.
authors.affiliation: Faculty of Science, University of South Bohemia, Branišovská 31, CZ-37005 České Budějovice, Czech Republic; Institute of Parasitology, Biology Centre of the Academy of Sciences of the Czech Republic, Branišovská 31, CZ-37005 České Budějovice, Czech Republic.
authors.forename: Patrik
authors.initials: P
authors.lastname: Kilian
authors.forename: James J
authors.initials: JJ
authors.lastname: Valdes
authors.forename: Daniel
authors.initials: D
authors.lastname: Lecina-Casas
authors.forename: Tomáš
authors.initials: T
authors.lastname: Chrudimský
authors.forename: Daniel
authors.initials: D
authors.lastname: Růžek
mesh_terms: D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000494:pharmacology; D001483:Base Sequence; D024882:Drug Resistance, Viral / Q000235:genetics*; D002141:Encephalitis Virus, California / Q000187:drug effects* / Q000235:genetics* / Q000302:isolation & purification; D014644:Genetic Variation; D016679:Genome, Viral / Q000235:genetics; D005838:Genotype; D006801:Humans; D008969:Molecular Sequence Data; D010802:Phylogeny; D012367:RNA, Viral / Q000235:genetics; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D014764:Viral Proteins / Q000235:genetics*
chemical_list: D000998:Antiviral Agents; C069882:L protein, Bunyamwera virus; D012367:RNA, Viral; D014764:Viral Proteins
keywords: 2,4-dioxo-4-phenylbutanoic acid; AKAV; Akabane virus; BUNV; Bunyamwera virus; CAL; CHATV; California complex; Chatanga virus; DPBA; ED; Genetic variability; INKV; Inkoo virus; L; LACV; La Crosse virus; Large genomic segment; M; ML; MP; N; NSs; ORF; OROV; OTU-like; Orthobunyavirus; PELE; RMSD; S; TAHV; VF; d(N); d(S); endonuclease domain; large genomic segment; maximum likelihood; maximum parsimony; medium genomic segment; non-synonymous nucleotide substitution rate; nonstructural protein encoded by S segment; nucleocapsid protein; open reading frame; oropouche virus; ovarian tumour-like; protein energy landscape exploration; root mean square deviation; small genomic segment; synonymous nucleotide substitution rate; temperature-sensitive; ts; valtice fever; Ťahyňa virus